18 November 2020

As the unrelenting stream of negative trial results for products targeting β-amyloid continues, attention is increasingly turning toward other possible approaches to disease modification in Alzheimer’s Disease (AD), including the revisiting of some rather old ideas.

It is now 30 years since epidemiological evidence started to emerge that people taking NSAIDs long term have a lower risk of developing and dying of AD, yet prospective interventional trials of a range of NSAIDs (e.g. aspirin, naproxen, celecoxib, corticosteroids) in established AD, mild cognitive impairment and in those at risk of AD have largely failed to provide evidence of benefit during prospective treatment [2].

It is clear that NSAIDs as a class have the potential to impact AD – quite apart from their ability to generically modulate the neuroinflammatory processes that pervade its pathophysiology, there exists specific evidence of desirable effects on disease-specific features such as amyloid precursor protein (APP) processing, fibrillary Aβ formation and the production of non-amyloidogenic secretases. 

Recently, it has been proposed that timing may be critical, with long-term non-specific anti-inflammatory therapy having the potential to be of benefit during the long prodrome of AD, but with immunomodulatory therapy targeted at more specifically AD-related targets becoming necessary as disease progresses. 

Furthermore, retrospective proteomic analysis of plasma samples from 351 participants with mild to moderate AD in a negative study of 1-years’ treatment with NSAID vs placebo has been shown to identify with 97-98% accuracy those whose inflammatory markers predicted a response to NSAIDs.  The authors hypothesized that previously conducted NSAID trials in AD were in fact successful for specific subgroups of patients and could have been ‘positive’ if such diagnostic markers had been used to select them [3].

If such proposals can be supported by further research then we may find ourselves in the regrettable position of having long possessed at least a partial answer to the scourge of AD without knowing it – although how Level 1 evidence can be obtained without undertaking decades-long clinical trials is a different challenge altogether.

References and further reading:  

  1. Benito-León J, Contador I, Vega S, et al. Non-steroidal anti-inflammatory drugs use in older adults decreases risk of Alzheimer’s disease mortality.  PLoS ONE 2019; 14(9): e0222505
  2. Imbimbo BP, Solfrizzi V, Panza F. Are NSAIDs useful to treat Alzheimer’s disease or mild cognitive impairment? Front. Aging Neurosci 2010; 2: Art. 19
  3. O’Bryant SE, Zhang F, Johnson LA, et al. A precision medicine model for targeted NSAID therapy in Alzheimer’s disease. J Alzheimers Dis 2018; 66(1): 97–104
  4. Zhang C, Wang Y, Wang D, et al. NSAID Exposure and Risk of Alzheimer’s Disease: An Updated Meta-Analysis from Cohort Studies.  Front. Aging Neurosci 2018; 10: Art. 83